The Portland cohort study of 24,000 women was completed in 2001 and specimen testing has now been completed. We observe (Dr. Schiffman) that the most important types of HPV, called HPV16 and HPV18, predict much high absolute risks of cervical cancer and precancer in prospective follow-up lasting 15 years, despite screening. The Portland cohort study is now effectively finished, with the final publications due this coming year. Other, nearly completed and large prospective projects include the ALTS clinical trial and the Guanacaste cohort analyses, both in the final testing and analyses phases. Based on HPV typing of all 20,000 specimens from the 5,000 ALTS participants, we are examining the diverse natural histories of the carcinogenic and non-carcinogenic HPV types, and the influences of co-factors. This study is still useful for validating new HPV tests, an effort led by Dr. Castle. Many data analyses are underway for the Guanacaste Project, for example, longitudinal analyses of HPV DNA, cytology, and visual appearance of the cervix among the 10,000 women during the 7 years of follow-up (Dr. Schiffman), and in-depth studies of HPV type variants and risk of viral persistence and progression focused particularly on HPV16 (Dr. Safaeian). We are finding that multiple infections, though very common, show little evidence of synergy or antagonism with regard to either persistence or neoplastic progression. Clearance typically occurs within 6 months to 2 years after first infection. We observe that if infections become inapparent, they pose very low subsequent risk of precancer, even if they re-appear briefly due to yet undefined lapse in immune control. There are several ancillary projects just completed as part of the investigations in Guanacaste, directed by several investigators working with Dr. Hildesheim. For example, genetic influences on persistence and progression are being studied by Dr. Wang. In other work, research continues on identifying and validating biomarkers of risk of progression. This includes the identification of novel tumor suppressor genes found to be methylated in cervical neoplasia. SUCCEED directed by Dr. Wang is focused on the identification of biomarkers of risk at each progressive disease stage, aimed to identify the molecular events that are necessary and sufficient for progression to cervical cancer. Frozen specimens, often multiple, from 2000 women with varying grades of cervical neoplasia (including the ectocervix, transformation zone, and endocervix) have already been collected. In a new study at the same center in Oklahoma, Dr. Wentzensen is investigating the earliest discernible transitions from HPV infection to CIN3. Dr. Castle launched an effort to validate HPV testing via self-sampling in the Mississippi Delta, a region with relatively high rates of cervical cancer. The project will investigate whether HPV screening might improve screening coverage and accuracy compared with conventional clinic-based cytology. Our newest cohort study also directed by Dr. Castle will be based on follow-up of 30,000 or more women found to be HPV DNA-positive during screening at Kaiser Northern California. Also, a cross-sectional study in Nigeria has been launched to investigate whether reported high prevalence of infection in older women is confirmed and, if so, to investigate why. Investigations on unusual age-specific HPV prevalence rates are very important for understanding HPV natural history and for designing rational screening programs. Finally, we are working on sharing the longitudinal data from NCI projects with collaborators for research and teaching, using a novel multi-media database system developed with engineers at the National Library of Medicine.